Solid forms and combination compositions comprising a beta-lactamase inhibitor and uses thereof

Inventors

Burns, Christopher J. • Pevear, Daniel C. • XERRI, Luigi • Henkel, Timothy • McGarry, Daniel • Rosen, Lawrence • Brenner, Gerald • Arlin, Jean-Baptiste • Fernandez Casares, Ana

Assignees

Crystallics BV • VenatoRx Pharmaceuticals Inc

Abstract

Described herein are crystalline forms of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid. In some embodiments, the crystalline forms are formulated for treating a subject in need thereof with a bacterial infection.

Core Innovation

The disclosure describes crystalline solid forms of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, dihydrochloride, including a monohydrate crystalline form (Form 1) and an anhydrous dihydrochloride form (Form 2). The solid forms are characterized using XRPD, VH-XRPD, HR-XRPD, dynamic vapor sorption, TG/MS, DSC, and determination of water content, together with XRPD peak lists and thermal/moisture behavior.

The disclosure further describes solubility determination in IPA/water, recrystallization to obtain the monohydrate, and impurity profiling using HPLC. It also describes pH-dependent aqueous solubility and physical stability under humidity/temperature conditions, including dehydration and conversion observations for the crystalline forms.

The solid-form work is expanded to polymorph screening yielding additional low-frequency forms (Forms 3–6) with mixed hydrate/solvate character, and conversion to Form 1 under stress/aging. The disclosure additionally addresses pharmaceutical compositions combining the crystalline solid forms, or related salts/solvates, of the compound with cefepime, including injectable liquid and powder-for-reconstitution formulations with optional excipients such as L-arginine and specified pH ranges.

In addition, the disclosure describes methods of treating bacterial infection by administering the pharmaceutical compositions containing the compound solid forms and cefepime, and reports combination efficacy testing, including MIC comparisons against beta-lactam-resistant organisms.

Claims Coverage

The independent claims cover an XRPD-defined monohydrate crystalline form of Compound 1-dihydrochloride and pharmaceutical compositions comprising that monohydrate form together with cefepime, with dependent refinements to XRPD peak sets, excipient inclusion, composition pH, and administration for treating bacterial infection in a subject. Across the cited independent claims, the inventive features center on XRPD-defined crystalline identity and co-formulation with cefepime.

The claims coverage centers on the XRPD-defined monohydrate crystalline identity of Compound 1-dihydrochloride and on pharmaceutical compositions that include this monohydrate together with cefepime, with optional L-arginine and treatment of bacterial infection by administration of the composition.

Stated Advantages

Documented Applications